Pyridothienodiazepines, methods for their preparing, pharmaceutical composition based on thereof and intermediate compounds

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to new biologically active derivatives of pyridothienodiazepine. Invention describes derivatives of pyridothienodiazepine of the general formula (I):

as a racemate or in form of enantiomers or diastereomers, or their mixture wherein R1 represents hydrogen atom or radical of the formula: R'1-NH-C(Y)- wherein R' represents phenyl radical optionally substituted with one or more similar or different substitutes taken among lower alkyl, lower alkoxy-group, lower alkylthio-group, lower alkoxycarbonyl, lower alkylsulfonyl, halogen atom, trifluoromethyl, trifluoromethyloxy-group, hydroxy-, nitro-, cyano-group, phenyl, phenoxy-group, cycloalkyl or heterocycloalkyl; R2 represents lower alkyl, trifluoromethyl or phenyl radical optionally substituted with one or more similar or different substitutes taken among hydroxy-group, halogen atom, lower alkyl or lower alkoxy-group; X and Y represent independently oxygen (O) or sulfur (S) atom; R3a represents hydrogen atom, lower alkyl, hydroxy-group or radical of the formula -OC(O)R'3a wherein R'3a represents alkyl radical comprising from 1 to 10 carbon atoms optionally substituted with radical of the formula: NR''3aR'''3a wherein NR''3a and R'''3a represent independently hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylcarbonyl or alkoxycarbonyl; R3b represents hydrogen atom or lower alkyl radical; R4 represents radical of the formula: -(CH2)n-CHR'4R''4 wherein n represents a whole number 0, 1, 2, 3, 4, 5 or 6; R'4 and R''4 represent independently hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkylalkyl, phenyl, pyridyl, phenylcarbonyl or adamantyl wherein indicated radicals are substituted optionally with one or more similar or different substitutes taken among hydroxy-group, halogen atom, trifluoromethyl, lower alkyl or lower alkoxy-group; A----B represents -C=N- or -C-N(R5)- wherein R5 represents hydrogen atom, amino-radical, lower alkylamino-group, di-(lower alkyl)-amino-group, cycloalkyl, heterocycloalkyl, guanidyl optionally substituted with nitro- or cyano-group, phenyl optionally substituted with one or more similar or different substitutes taken among alkyl or alkoxyalkyl wherein indicated alkyl or alkoxyalkyl are substituted optionally with oxy- or amino-group; indolyl or radical of the formula: -NH-C(O)-(CH2)c-NH-C(O)(CH2)d-NH2; p represents a whole number 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; c and d represent independently a whole number 0, 1, 2 or 3; or salts of these compounds. Also, invention describes methods for preparing compounds of the general formula (I), pharmaceutical composition based on compounds of the general formula (I) eliciting activity to inhibit binding somatostatin-14 and an intermediate compound of the formula (2) given in the invention description. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

17 cl, 70 ex

 

The present invention relates to new pyridodiazepines, the way they are received and containing pharmaceutical compositions. Data pyridodiazepines particularly useful for the treatment of pathological conditions or diseases that involve one (or more) of somatostatin receptors.

Somatostatin (SST) was first identified as a factor inhibiting the secretion of growth hormone (Brazeau P. et al., Science, 1973, 179, 77-79). This substance is known in two forms - somatostatin 14 and somatostatin 28 and is widely distributed in animals and in humans. The peptides of this family also act as neurotransmitters in the brain (hypothalamus, sensory neurons, cerebral cortex) (Reisine T. et al., Neuroscience, 1995, 67, 777-790; Reisine et al., Endocrinology, 1995, 16; 427-442) and in endocrine organs (pancreas, intestines, kidneys, salivary glands, cells of the thyroid gland and so on). The biological activity of somatostatin directly depends on a family of five recently cloned receptors.

Among the pathological conditions associated with somatostatin (J.P. Moreau et al., Life Sciences, 1987, 40, 419; A.G. Harris et al., The European Journal of Medicine, 1993, 2, 97-105), can be mentioned, for example, acromegaly, pituitary adenomas that do not secrete growth hormones, pituitary adenomas that secrete thyroid-stimulating hormone, Cushing disease, gonadotropinum and prolactinoma, catabolic, Bobo the major effects of glucocorticoids, pituitary adenomas without endocrine secretion, insulin-dependent diabetes, diabetic retinopathy, diabetic nephropathy, hyperthyroidism, gigantism, endocrine tumors of the gastrointestinal tract and pancreas, including carcinoid syndrome, Vipoma, insulinoma, nesidioblastosis, hyperinsulinemia, glucagonoma, gastrinoma and the syndrome of Zollinger-Ellison, STH-RF-Ohm, and acute bleeding from varicose blood vessels of the esophagus, gastro-esophageal reflux, gastroduodenal reflux, pancreatitis, entero-cutaneous fistula and fistula of the pancreas, but also diarrhea, persistent diarrhea in acquired immunodeficiency syndrome, chronic secretory diarrhea, diarrhea associated with the syndrome of inflamed bowel disorders associated with gastrin-releasing peptide, secondary pathology, transplantation of the intestine, portal hypertension and bleeding varicocele in patients with cirrhosis, gastrointestinal bleeding, bleeding from gastroduodenal ulcers, Crohn's disease, systemic sclerosis, drop syndrome, the syndrome of the small intestine, hypotension, scleroderma and modular carcinoma of the thyroid gland, diseases associated with cellular hyperproliferation, such as cancer, and more specifically breast cancer, prostate cancer, thyroid cancer, and cancer pojulu the face-to-face cancer and colorectal cancer, the fibrosis and, more specifically fibrosis, skin fibrosis, Central nervous system, as well as such (fibrosis) of the nose and fibrosis induced by chemotherapy, and other treatment, such as, for example, severe headaches, including headache associated with pituitary tumors, pain, anxiety attack, chemotherapy, scarring, renal insufficiency arising from delayed development, obesity and delayed development associated with obesity, delayed development of the uterus, skeletal dysplasia syndrome Noonan syndrome stop breathing during sleep, graves ' disease, polycystic ovarian disease, pancreatic pseudocyst and ascites, leukemia, meningioma, cachexia in cancer, braking .pylori, psoriasis, osteoporosis, and Alzheimer's disease.

These benzodiazepines are affinity and selectivity for somatostatinoma receptors. Clinical application of natural somatostatin and its peptide analogs is often limited. Indeed, the main cause is often poor bioavailability by oral route of administration and low selectivity (Robinson, C., Drugs of the Future, 1994, 19, 992; Reubi, J.C. et al., TIPS, 1995, 16, 110). Due to its ones of the connection structure of the present invention, agonists or antagonists of somatostatin, seem to be less prone to metabolic degrade the AI, than the natural hormone and peptide analogues, and should, therefore, have a greater duration of action. These compounds can be advantageously used for the treatment of pathological conditions or diseases, such as presented above, and are involved in one (or more) somatostatinoma receptors.

The aim of the present invention are therefore compounds of General formula I

in racemic or enantiomeric or diastereoisomeric form, or a mixture thereof and in which

R1represents a hydrogen atom or a radical of the formula R’1-NH=C(Y)-;

R’1represents aryl or heteroaryl radical, and aryl and heteroaryl radicals are optionally substituted;

R2represents lower alkyl, trifluoromethyl or phenyl radical, optionally substituted;

X and Y independently represent O or S;

R3Arepresents a hydrogen atom, lower alkyl, hydroxyacyl or a radical of the formula-OC(O)R’3A;

R’3arepresents an alkyl radical containing from 1 to 10 carbon atoms, optionally substituted;

R3brepresents a hydrogen atom or a lower alkyl radical;

R4represents a radical of the formula - (CH2)n-CHR’4R4;

n represents an integer 0, 1, 2, 3, 4, 5 or 6;

R’ 4and R4independently represent a hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkenyl, aryl, lower arylalkyl, heteroaryl, lower heteroallyl, arylcarbamoyl or adamantly radicals, and these radicals are optionally substituted;

And--is-C=N - or-C-N(R5)-;

R5represents a hydrogen atom, lower alkyl, lower alkenyl or a radical of the formula-C(O)-(CH2)pR’5-;

R’5represents a hydrogen atom, aminoacyl, lower alkylamino, di(lower alkyl)amino, cycloalkyl, heteroseksualci, guanidyl, optionally substituted by nitro or cyano, optionally substituted aryl, heteroaryl or a radical of the formula-NH-C(O)-(CH2)c-NH-C(O)-(CH2)d-NH2;

p represents an integer 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

C or d independently represent an integer 0, 1, 2 or 3;

or salts of these compounds.

More specifically the present invention are compounds of General formula I, as described above, in which

identical or different substituents aryl or heteroaryl radical represented by R’1selected from the following radicals: lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, lower alkylsulfonyl, halo, trifloromethyl, cryptometrics, hydroxy, nitro, cyano, aryl, Ari is hydroxy, cycloalkyl or geterotsiklicheskie;

identical or different substituents of phenyl radical represented by R2selected from: hydroxy, halogen, lower alkyl or lower alkoxyalkyl;

identical or different substituents alkyl radical represented by R’3aselected from the following radicals: cycloalkyl; geterotsiklicheskie; aryl; heteroaryl; guanidino, optionally substituted by nitro or cyano; a radical of the formula NR3AR’’3Ain which R3aand R’’3aindependently represent a hydrogen atom, lower alkyl, aryl, lower arylalkyl, lower heteroallyl, alkylsulphonyl or alkoxycarbonyl;

identical or different substituents of the alkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaromatic, arylcarbamoyl or Adamantine radical, independently represented by R’4and R4selected from: hydroxy, halo, trifloromethyl, lower alkyl or lower alkoxy;

identical or different substituents of the aryl represented by R’5selected from the following radicals: alkyl or alkoxyalkyl, and data alkyl or alkoxyalkyl radicals optionally substituted hydroxy or amino group.

In the definitions above, the term "halo" represents a fluorine, chlorine, bromine or iodine, preference is sustained fashion chlorine, fluorine or bromine. The expression "lower alkyl" preferably represents alkyl having from 1 to 6 carbon atoms, linear or branched and, in particular, alkyl having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, but may also represent pentyl, isopentyl, hexyl or isohexyl.

The lower alkoxy radicals may correspond to the alkyl radicals mentioned above, and may represent a methoxy, ethoxy, propoxy or isopropoxy, as well as linear, secondary or tertiary, butoxy. The term "alkylthio" preferably designates the radicals in which the alkyl radical defined as above, and represents, for example, methylthio, ethylthio. The term "lower alkenyl" preferably means alkanniny radical having from 1 to 6 carbon atoms, such as vinyl, allyl, butenyl. The term "alkoxyalkyl" preferably designates the radicals in which the alkoxy and alkyl are defined as above.

The term "cycloalkyl" preferably denotes a ring cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The expression "heteroseksualci" denotes a saturated cycloalkyl containing from 2 to 7 carbon atoms and at least one heteroatom. This radical can contain several identical or different hetaeras the atoms. Preferably the heteroatoms are selected from oxygen, sulfur or nitrogen. As examples of geterotsiklicheskie can be mentioned the following: pyrolidine, imidazolidinone, pyrazolidinone, isothiazolinone, thiazolidinone, isoxazolidinone, oxazolidinone, piperidino, pieperazinove or morpholino ring.

The expression "aryl" represents an aromatic radical consisting of rings or condensed rings, such as, for example, phenyl or nattily radical. The term "aryloxy" preferably designates the radicals in which the aryl radical is defined as above, such as, for example, phenoxy. The expression "heteroaryl" denotes an aromatic radical consisting of rings or condensed rings with at least one ring containing one or more identical or different heteroatoms selected from sulfur, nitrogen or oxygen. As an example, the heteroaryl radical may be mentioned the following radicals: thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolin, thiazolyl, ethoxalyl, isoxazolyl, oxazolyl, pyridyl, pyrazinyl, pyrimidyl, benzothiazyl, benzofuran or indolyl.

Lower arylalkyl radicals designate radicals in which, respectively, aryl and lower alkyl radicals are defined as above, such as, for example, benzyl, Hairdryer is Teal or naphthylmethyl. Lower heteroallyl radicals designate radicals in which, respectively, heteroaryl and lower alkyl radicals are defined as above, such as, for example, indolylmethane, thienylmethyl, furylmethyl. The term "lower cycloalkenyl" refers to radicals in which, respectively cycloalkyl and lower alkyl radicals are defined as above.

The term "alkylsulfonyl" preferably designates the radicals in which the alkyl radical defined as above. Similarly, the terms "arylcarbamoyl", "alkoxycarbonyl and alkylaryl" preferably represent radicals in which aryl, CNS and alkyl radicals are defined as above. The terms "lower alkylamino" and "di (lower alkyl)amino" preferably represent radicals in which the alkyl radicals are defined as above, such as, for example, methylamino, ethylamino, dimethylamino, diethylamino or (methyl)(ethyl)amino.

In accordance with the definition of the different groups of the compound of formula I, as described above, may have one or more asymmetric carbons. The invention relates to compounds of formula I, as defined above, which may be in racemic, enantiomeric or diastereoisomeric form, or a mixture thereof.

A more specific aim of the present invention are compounds of the General formula I, as described above, in which

R’1represents aryl radical, optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy, trifluoromethyl or nitro;

R2represents a lower alkyl radical or phenyl radical, optionally substituted by one or more groups, equal or different, selected from halo or lower alkyl;

R3Arepresents a hydrogen atom, hydroxyacyl or a radical of the formula-OC(O)R’3A;

R’3arepresents a linear or branched alkyl containing from 1 to 6 carbon atoms, optionally substituted by one or more substituents, equal or different, of formula NR3aR’’3ain which R3Aand R’’3aindependently represent a hydrogen atom, lower alkyl or alkoxycarbonyl;

R3brepresents a hydrogen atom;

R’4and R4independently represent a hydrogen atom, lower alkyl, cycloalkyl, aryl, heteroaryl, arylcarbamoyl or adamantly radical;

And--is-C=N,

in a preferred variant

R’1represents a phenyl radical, optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy, crypto is methyl or nitro;

R2represents lower alkyl or phenyl radical, optionally substituted by one or more groups, equal or different, selected from: methyl, chlorine or fluorine;

R’3arepresents a linear or branched alkyl containing from 1 to 6 carbon atoms, optionally substituted by one or more amino groups;

R’4and R4independently represent a hydrogen atom, lower alkyl, cyclohexyl, phenyl, pyridyl, phenylcarbinol or substituted;

More specifically, the aim of the present invention are compounds described in the examples below, in which a--b is-C=N-, in particular compounds in which the radicals R1; R’1; Y; R2; R3A; R3b; X; n; R’4; R4have respectively the following values:

N; -; -; 2-Cl-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; S; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N;; 2; N; Phe;

N; -; -; 2-Cl-Phe; N; N; O; 0; N; phenylcarbinol;

N; -; -; 2-Cl-Phe; H; N; O; 0; N; Phe;

N; -; -; 2-Cl-Phe; N; N; O; 0; S; cyclohexyl;

N; -; -; 2-Cl-Phe; N; N;; 4; N; N;

N; -; -; 2-Cl-Phe; N; N;; 2; Phe; Phe;

N; -; -; 2-Cl-Phe; N; N;; 2; Me; Me;

N; -; -; 2-Cl-Phe; N; N; O; 0; N; substituted;

N; -; -; 2-Cl-Phe; N; N; O; 1; N; pyridyl;

N; -; -; Phe; N; N; O; 1; N; Phe;

N; -; -; 4-Cl-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-F-Phe; N; N; O; 1; N; Phe;

N; -; -; 4-F-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-Me-Phe; N; N; O; 1; N; Phe;

N; -; -; tert-butyl; N; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe;IT; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; OC(O)-(CH2)6NH2; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 2; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; S; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; N; phenylcarbinol;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 4; N; N;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; S; cyclohexyl;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 2; Phe;

Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; substituted;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 1; H; pyridyl;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 4-Cl-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 4-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-F3With-h; O; 4-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Me-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; tert-butyl; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; OH; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; -OC(O)-(CH2)6NH2; H;; 1; H; Phe.

A more specific aim of the invention are the compounds is of the General formula I, as described above, in which

R’1represents aryl radical, optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy or nitro;

R2represents a phenyl radical, optionally substituted by one or more identical or different holography;

R3Aand R3brepresent a hydrogen atom;

R’4and R4independently represent a hydrogen atom, lower alkyl or aryl radical;

And--is-C=N(R5)-;

R5represents a hydrogen atom, a lower alkanniny radical or a radical of the formula-C(O)-(CH2)p-R’5;

in a preferred variant

R’1represents a phenyl radical, optionally substituted by one or more substituents, identical or different, chosen from the following radicals: lower alkoxy or nitro-group;

R2represents lower alkyl or phenyl radical, optionally substituted by chlorine;

R’4and R4independently represent a hydrogen atom, lower alkyl or phenyl;

R5represents a hydrogen atom, pentenyl or a radical of the formula-C(O)-R’5;

R’5represents a hydrogen atom, aminoacyl, cyclopentyl, indolyl, a radical of the formula-NH-C(O)-CH2-NH-C(O)-CH2-NH 2or phenyl, optionally substituted by one or more substituents, the same or different, selected from alkyl or alkoxyalkyl, and these alkyl and alkoxyalkyl optionally substituted hydroxy and amino group.

More specifically the aim of the invention are compounds described in the examples below, in which a--b is-N(R5)-, in particular compounds in which the radicals R1; R’1; Y; R2; R3a; R3b; X; R5; n; R’4; R4have respectively the following values:

N; -; -; 2-Cl-Phe; N; N; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; N;; 2; Me; Me;

N; -; -; 2-Cl-Phe; N; N; -CH2CH=C(Me)2;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminohexanoic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminophenylarsonic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; indolylmethane;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminobutyryl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; propylboronic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; cyclopentanecarbonyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; phenylpropionyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; phenylethylamine;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; 4-(L-alkanoyloxy)benzylcarbamoyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; 4-aminomethylpropanol;; 1; N; Phe;

N; -; -; Phe; N; N; NH2-CH2-C(O)-NH-CH2-C(O)-NH-CH2-C(O) -;; 2; Me; Me;

N; -; -; neopentyl; N; N; aminohexanoic;; 1; N; Phe;

N; -; -; isobutyl; N; N aminohexanoic; About; 1; N; Phe;

N; -; -; isobutyl; N; N; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; N;; 4; N; N;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; -CH2CH=C(Me)2;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminohexanoic;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; propylboronic;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; cyclopentanecarbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; phenylpropionyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; phenylethylamine;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminobutyryl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; indolylmethane;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminophenylarsonic;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; N; N; NH2-CH2-C(O)-NH-CH2-C(O)-NH-CH2-C(O) -;; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; N; N; aminohexanoic;; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; neopentyl; N; N; aminohexanoic;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; isobutyl; N; N; aminohexanoic;; 1; N; Phe.

The compound of formula (I) in accordance with the invention, in which A--b is-C=N-, R1is a hydrogen atom and R3ais a hydrogen atom or alkyl and RA is hiccuping, can be obtained by the coupling of compounds of formula (1)

in which R2, R3a, R3bhave the meanings specified above, a R’ represents lower alkyl or lower arylalkyl, with connection R4Z, in which R4has the meaning specified above, Z represents a detachable group, in the presence of a strong base to obtain the compounds of formula (2)

in which X represents an oxygen atom, and which may then be subjected to reaction with theaterwomen reagent to obtain the compound (2)in which X represents a sulfur atom, the compound (2)in which X represents an oxygen atom or sulfur, is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I).

Upon receipt of the compounds (2), in which X represents an oxygen atom, the compounds of formula (1) is subjected to the action of a strong base, such as sodium hydride, in an inert solvent, such as, for example, tetrahydrofuran or dimethylformamide, at a temperature of about 20°C. Connection R4Z then added to the reaction mixture at a temperature of about 20°C, then the reaction mixture is heated to about 80°C. Detachable group Z connection R4Z can be, for example, mesilate, tosylate or halogen atom (before occhialino a chlorine atom or bromine). Obtaining the compounds (2), in which X represents a sulfur atom, starting from compounds (2), in which X represents an oxygen atom, can be performed at a temperature of about 80°With theaterwomen agent such as pentasulfide phosphorus, in a solvent such as pyridine.

Removing protection from carbamate, which does not affect the remainder of the molecule can be performed in accordance with known methods unprotect (T.W. Greene et al., Protective Groups in Organic Synthesis, Wiley-Interscience, 1991). Thus, in the case when R’ represents a linear alkyl group (such as ethyl), or arylalkyl group (such as benzyl), removing the protection of the carbamate can be performed by stirring the reaction mixture at ambient temperatures in a highly acidic environment, such as, for example, Hydrobromic acid (33% in acetic acid). When R’ represents more than zatrudnieniu alkyl group (such as tert-butyl), the reaction can be carried out in triperoxonane acid in an inert solvent, such as dichloromethane, at a temperature of about 20°C.

The products of formula (1) can be obtained in accordance with the method described in patent FR 2645153 or in accordance with the same methods.

Certain products of the formula R4Z is, in General, are commercially available (for example, from firms Acro or Aldrich); others can be obtained from an alcohol of formula R4-OH in an inert solvent, such as dichloromethane, influence of, for example, Teilhard in the presence of triethylamine or triphenylphosphine and chetyrehpostovye carbon.

The compound of formula (I) in accordance with the invention, in which A--b is C=N, R1is an oxygen atom and R3ais hydroxy, can be obtained by oxidation of compounds of formula (2), as described above, in an inert solvent to obtain compounds of formula (3)

in which R2, R3b, R4, R’ and X have the meanings indicated above,

the compound obtained of the formula (3) is treated with acetic anhydride to obtain a compound of the formula (4)

in which R2, R3b, R4, R’ and X have the meanings indicated above,

connection (4) then amyraut to obtain the compounds of formula (5)

in which R2, R3b, R4, R’ and X have the meanings indicated above,

the compound (5) at the final stage is subjected to reaction withdrawal carbamazapine group to obtain the corresponding compound of formula (I)in which R1is H and R3a- hydroxyacyl.

Oxidation of compound (2) at the level of imine diazepine can be performed using the PR is ancescao oxidizing agent, such as, for example, metallocarboxypeptidase acid, at a temperature of about 20°in an inert solvent such as dichloromethane or 1,2-dichloroethane. The reaction of the compound (3) with acetic anhydride is the type of rearrangement Polonovski (N.W. Gilman et al., SoC., 1990, 112, 3969-3978), which can be performed at a temperature of about 70°C. the saponification Reaction of the compound (4) can be effected by the action of an inorganic base, such as, for example, sodium hydroxide or lithium hydroxide, in a lower aliphatic alcohol (e.g. methanol, ethanol) at a temperature of about 20°C.

The compound of formula (I) in accordance with the invention, and in which A--b is C=N, R1is a hydrogen atom and R3a- OC(O)-R'3acan be obtained by the coupling of compounds of formula (5)as above, with an acid of the formula R'3a(O)HE, in which R’3ahas the meaning specified above, to obtain compounds of formula (6)

in which R2, R'3a, R3b, R4, R’ and X have the meanings indicated above,

the obtained compound (6) are then subjected to reaction withdrawal carbamazapine group to obtain the corresponding compounds of formula (I)in which R1is H and R3a- radical-OC(O)-R'3a.

The conversion of compound (5) compound (6) OS, the effect in terms similar to those of the esterification reaction, known to experts in the field; thus, it can be performed at a temperature of about 20°in an inert solvent such as dichloromethane or 1,2-dichloroethane.

The compounds of formula (I) in accordance with the invention, in which A--b is C=N, R1is a radical of the formula R’1-NH-C(Y), can be obtained in accordance with the method, which lies in the interaction of the corresponding compounds of formula (I)in which R1represents a hydrogen atom, with a compound of the formula

in which R’1and Y have the values specified above for the formation of selected compounds of formula (I).

Obtaining the compounds of formula (I)in which R1represents the radical R’1-NH-C (Y), adding the compounds of formula (7) to the compound of formula (I)in which R1represents a hydrogen atom, easily doable at a temperature of about 20°in a chlorinated solvent such as dichloromethane or 1,2-dichloroethane. The products of formula (7) generally commercially available or can be obtained by the interaction of the amine with (thio)phosgene in accordance with methods known to experts in this field.

The compounds of formula (I) in accordance with the invention, and in which A--b is C-N(R5)-, R1and R5- hydrogen atoms and R3ais a hydrogen atom or an alkyl radical, can be obtained by the action of a mild reducing agent in an acidic environment on the connection formulas (2), as described above, to obtain compounds of formula (8)

in which R2, R3a, R3b, R4, X and R’ have the meanings specified above,

the obtained compound (8) is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom.

When reconnecting (2) to obtain compound (8) can be used mild reducing agent, such as cyanoborohydride sodium in a solvent such as a lower alcohol solvent (e.g. methanol, ethanol)at a temperature of about 20°C.

The compound of formula (I) in accordance with the invention, and in which A--b is C-NR5, R1represents a hydrogen atom, R3ais a hydrogen atom or alkyl radicals and R5is alkanniny radical, can be obtained by the coupling of compounds of formula (8)as above, with the compound of the formula Z R5in which R5has the meaning specified above, a Z’ represents a detachable group, in the presence of a strong inorganic base in an inert solvent for p is obtaining compounds of formula (9)

in which R2, R3a, R3b, R4, X, R’ and R5have the meanings specified above,

the obtained compound (9) is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom.

Obtaining the compounds (9), starting from compound (8)can be performed through the action of sodium hydride in a solvent such as tetrahydrofuran, at a temperature of about 60°C.

Detachable group Z in the compound Z R5can be mesilate, tosylate or halogen atom.

The compound of formula (I) in accordance with the invention, and in which A--b is C-N(R5)-, R1represents a hydrogen atom, R3ais a hydrogen atom or an alkyl radical and R5represents a radical C(O)-(CH2)p-R’5can be obtained by the coupling of compounds of formula (8)as above, with an acid of the formula R’5-(CH2)p-C(O)IT, in which R’5and p have the meanings indicated above, to obtain the corresponding compound of formula(10)

in which R2, R3a, R3b, R4, X, R’, R and R’5have the meanings specified above,

the obtained compound (10) is subjected to reaction withdrawal carbamazapine group to obtain the desired about the ukta (I), in which R1represents a hydrogen atom.

The reaction of the compound R’5-(CH2)p-C(O)HE with compound (8) can be carried out in conditions similar to the conditions of the reaction of formation of the peptide bond. It can be performed at a temperature of about 20°in an inert solvent such as dichloromethane or 1,2-dichloroethane.

The compound of formula (I) in accordance with the invention, and in which A--b is-C is-N(R5)-, R1is a hydrogen atom and R3a- the hydroxyl radical, can be obtained by reduction of compounds of formula (4) to obtain the compounds of formula (11),

in which R2, R3b, R4, X and R’ have the meanings specified above,

the obtained compound (11)

or is subjected to reaction with subsequent saponification reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1and R5represent a hydrogen atom;

or treated with compounds of the formula halo,-R5in which R5is alkanniny radical, or acid

formula R’5-(CH2)p-C(O)IT, in which R’5and p have the meanings indicated above, to obtain compounds of formula (12)

in which R2, R3b, R4X and R have the meanings stated above and R5predstavljaet respectively of alkenyl or the radical R’ 5-(CH2)p-C(O)O-,

the compound obtained (12) at the final stage is subjected to a saponification reaction and then the reaction removing carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom, a R5alkenyl or the radical R’5-(CH2)p-C(O)-.

The compound of formula (I) in accordance with the invention, in which A--b is-C is-N(R5)-, R1is a hydrogen atom and R3a-radical-OC(O)-R3acan be obtained by reduction of compounds of formula (6) to obtain the compounds of formula (13),

in which R2, R’3A, R3b, R4, H and R’ have the meanings specified above,

the compound obtained (13)

or is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1and R5represent a hydrogen atom;

any process connection halo,-R5in which R5represents alkenyl, or acid of the formula R’5-(CH2)p-C(O)IT, in which R’5and p have the meanings indicated above, to obtain compounds of formula (14)

in which R2, R’3A, R3b, R4X and R have the meanings stated above and R5represents respectively alkenyl or the radical R’5-(CH 2)p-C(O)-,

the obtained compound (14) at the final stage is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom, a R5accordingly, alkenyl or the radical R’5-(CH2)p-C(O)-.

Conditions of accession of the radical R5(other than N) to the nitrogen atom of benzodiazepines (11) and (13) are identical reaction conditions to obtain the compounds (9) and (10). The reaction removal carbamazapine group(5), (6), (8), (9), (10), (13) and (14) are the same as described above; the radical R ' is selected in accordance with other features present in the molecule, and to ensure selective removal protection urethane group, R’OC(O)N-.

The compounds of formula (I) in accordance with the invention, in which A--b is-C is-N(R5)and R1represents a radical of the formula R’1-NH-C(Y)can be obtained by the coupling of compounds of formula (7) R’1-NH=C=Y, in which R’1and Y have the meanings stated above, with a corresponding compound of formula (I)in which R1represents a hydrogen atom, to obtain the selected compounds of formula (I).

The compounds of formula (2) are new. The aim of the invention are also the products of formula (2) as new industrial products and, in particular, as new industrial products, art is meant to produce compounds of formula (I) in accordance with the invention.

The compounds I of the present invention possess useful pharmacological properties. Thus, it was found that the compounds I of the present invention have high affinity to one or more somatostatin receptors. They can be used as selective or non-selective ones agonists or antagonists of somatostatin.

Compounds of the present invention can thus be used for various therapeutic purposes. Their beneficial use for the treatment of pathological conditions or diseases, as presented above, are involved in one (or more) of somatostatin receptors.

Illustration of the pharmacological properties of the compounds of the invention will be presented below in the experimental part.

The purpose of this application are also the products of formula (I) as a drug, as described above, as well as additive salts of these products of formula (I) with pharmaceutically acceptable inorganic or organic acids, as well as pharmaceutical compositions containing as active ingredient at least one of the drugs, as described above, in combination with a pharmaceutically acceptable carrier.

The pharmaceutical composition may be in solid form, for example in the form of powders, granules, tablets, relatinoships or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine and wax.

Pharmaceutical compositions containing the compound in accordance with the invention, can also be presented in liquid form, such as, for example, solutions, emulsions, suspensions or syrups. Appropriate liquid supports can be, for example, water, organic solvents such as glycerol or glycols, and mixtures thereof in various proportions with water added thereto pharmaceutically acceptable oils or fats. For intramuscular, intraperitoneal or subcutaneous injection may be used in a sterile liquid composition and sterile compositions can also be administered intravenously.

All technical and scientific terms used herein have the meanings known to specialists in this field. Similarly, all patents (or patent applications), and other bibliographic reference materials are included as references.

The following examples are presented to illustrate the above procedures and in no way should be considered as limitations of the scope of this invention.

Experimental part

NOTE THE P 1.

5-(2-Chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl)-2H-pyrido[4’,3’: 4,5]thieno[2,3-e]-1,4-diazepin-2-he

1st stage: Ethyl

5-(2-chlorophenyl-1,3,6,7,8,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylat

18 g of ethyl 5-(2-chlorophenyl)-1,3,6,7,8,9-hexahydro-2-oxo-8H-pyrido[4’,3’:4,4]thieno[2,3-e]-1,4-diazepin-8-carboxylate (4,46 mmol) dissolved in argon atmosphere in 180 ml of anhydrous dimethylformamide. Added 60% sodium hydride (1,784 g of 4.46 mmol), after which the reaction medium is heated for approximately 30 minutes at 50°s to stop shedding. The reaction mixture is cooled to a temperature of about 20°C, after which the syringe add 2-primatives (6.2 ml, of 4.46 mmol). Conduct stirring for 16 hours at 23°C, after which the reaction mixture is then poured into a saturated solution of ammonium chloride (400 ml). Produce extraction with ethyl acetate (2×500 ml). The organic phase is dried over magnesium sulfate, then the solvent is evaporated on a rotary evaporator. After purification by chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 0-100 to 20-80), the fractions containing only the product are evaporated and the desired product is obtained in the form of white amorphous powder (20,3 g 89%).

Melting point: 70-78°C.

1H NMR (400 MHz, Dl3that δ)with 1.07(m, 3H), of 1.46(m, 1H), 1.93 and-of 1.97(m, 1H), 2,85(m, 2H), 3.0 a(m, 1H), 3,69(m, 2H), 3,69 (m, 1H), was 4.02(m, 2H), to 4.38(m, 2H), 4,73(m, 2H), 7,20-7,49(m, N).

IR (cm-1): 3427, 2978, 2927, 1686 (ν C=O carbamate), 1678 (ν lactam), 1231, 1115, 761.

2nd stage: 5-(2-Chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl)-2H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

The mixture containing the compound obtained in the previous phase (20,3 g, 0.04 mol)in a solution of 33% Hydrobromic acid in acetic acid (500 ml) is stirred for 12 hours at a temperature of about 20°C. the Reaction mixture is heated for 3 hours at 40°C, after which the acid is evaporated on a rotary evaporator. The oil obtained absorb 300 ml of water, then gradually and carefully add a saturated solution of sodium bicarbonate (300 ml). The extraction is carried out with dichloromethane (2×300 ml), then dried over magnesium sulfate and the solvent is evaporated to obtain the desired product in the form of crimson and blue amorphous powder (17 g, 97%).

Melting point: 70-78°C.

IR (cm-1): 3427, 2978, 2927, 1678 (ν lactam), 1231, 1115, 761.

HPLC (UV): 99%.

EXAMPLE 2. 5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl}-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5] thieno[2,3-e]-1,4-diazepin-8-carbothioamide

A mixture containing 5-(2-chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl)-2H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-1-he (0.2 g, 0.46 mmol) and 4-methoxy-2-nitrostyrene (0,096 g, 0.46 mmol) in 4 ml of anhydrous d is chlormethine, stirred for 3 hours at a temperature of about 20°C in argon atmosphere. To the reaction mixture was added ether (2 ml) and produce stirring for about thirty minutes and the precipitate discarded. The solid is filtered on a Frit and washed with isopropyl ether (2×5 ml) and then with isopentane (5 ml). After drying under vacuum at a temperature below 100°To get the desired product in the form of a yellow powder (of € 0.195 g, 66%).

Melting point: 145-150°C.

1H NMR (400 MHz, Dl3that δ): 1,70(m, 1H), 2,12(m, 1H), 2,81-is 2.88(m, 2H), 3,55(m, 1H), 3,74(m, 1H), 3,84(s, 3H), of 3.96 (m, 1H), 4,23(m, 1H), to 4.41(m, 1H), 4,73-4,82(m, 2H), 5,42(m, 1H), 7,20-7,51(m, N), 9,49(, 1H).

IR (cm-1): 3427, 2978, 2927, 1678 (ν C=O lactam), 1530, 1210, 1030.

HPLC (UV): 99%.

EXAMPLE 3. 5-(2-Chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl)-2H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-tion

1st stage: Ethyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-1-(2-phenylethyl)-2-thioxo-8H-pyrido[4’,3’:4,5] thieno[2,3-e]-1,4-diazepin-8-carboxylate

A mixture containing ethyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate (0.97 g, at 1.91 mmol) and pentasulfide phosphorus (0,425 g, at 1.91 mmol) in pyridine (10 ml)is heated at a temperature of about 85°C for 5 hours. The temperature returns to about 20°and the residue is filtered on a Frit. Contained in the filtrate pyridine issue the mandate on a rotary evaporator (with toluene). Add dichloromethane (40 ml) and the organic phase is washed, dried over magnesium sulfate and the solvent is evaporated. Then the resulting powder was heated for 1 hour under reflux with acetonitrile (100 ml). After evaporation of the solvent on a rotary evaporator perform purification via chromatography on a column of silica (eluent: mixture of ethylacetate: from 20-80 to 45-55). The fractions containing only the product evaporated to obtain the desired product in the form of a yellow powder (0.1 g).

1H NMR (400 MHz, Dl3that δ): 0,84(m, 3H), 1,49(m, 1H), 1,95 of 1.99(m, 1H), 2,8-of 3.12(m, 3H), 3,70(m, 2H), 4,03-4,19(m, 2H), or 4.31-4,34(m, 2H), 4,80(m, 1H), 4,98-of 5.05(m, 1H), lower than the 5.37(d, 1H), 6,95-to 7.67(m, N).

IR (cm-1): 3427, 2978, 2927, 1701 (ν C=O lactam), 1592, 1384, 1296, 1225, 761.

2nd stage: 5-(2-Chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl)-2H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-tion

The compound obtained in the previous phase (0.1 g, to 0.19 mol) in Hydrobromic acid, diluted to 33% in acetic acid (30 ml), stirred for 3 days. Acid is evaporated on a rotary evaporator with toluene. Add dichloromethane (30 ml) and saturated sodium bicarbonate solution (50 ml). Produce stirring for several hours, after which the organic phase is extracted and dried over magnesium sulfate, and the solvent is evaporated to obtain the desired product is A.

EXAMPLE 4. 5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl)-1-(2-phenylethyl)-2-thioxo-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

86 mg of 5-(2-chlorophenyl)-1,3,6,7,8,9-hexahydro-1-(2-phenylethyl) -2H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-thione enter into reaction with 4-methoxy-2-nitrostyrene (0,040 g 0,19 mmol) in 2 ml dichloromethane at a temperature of about 20°C. the Reaction mixture is stirred for 2 hours and add isopropyl ether (3 ml) and the precipitate discarded. After filtration on a Frit and washing with isopropyl ether (2×3 ml) and isopentane (5 ml) spend chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 20-80 40-60). After evaporation of the fractions containing only the product, get the desired product in the form of an orange powder (0.03 g, 24%).

Melting point: 152°C.

HPLC-MS: 99% at 230 nm (MN+ found 662,1; MN+ theoretical 662,2).

EXAMPLE 5. 5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido [4’,3’:4,5] thieno[2,3-e]-1,4-diaaepam-2-he

1st stage: tert-Butyl 5-(2-chlorophenyl-1,2,3,6,7,9-hexahydro-4-oxide-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate

tert-Butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo - 1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate (22 g, 41 mmol) dissolved in 23°in 1,2-dichloroethane (320 ml). Add 85% metallocarboxypeptidase acid (21,6 g, 0.1 mol). Produce stirring for 24 hours at 23°With, then add 5N. the sodium hydroxide solution (400 ml). After desantirovaniya the organic phase is washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. After purification by chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 50-50 to 80-20) the fractions containing only the product is evaporated. The obtained solid is stirred in a mixture of solvents: isopropyl ether-isopentane (20-80). After filtration on a Frit and wash isopentane get the desired product in the form of a white powder (5.9 g, 26%).

1H NMR (400 MHz, Dl3that δ): 1,35(s, N), a 1.96(m, 1H), 2,87-of 3.07(m, 3H), 3,70(m, 1H), 3,88(m, 1H), 4,30(m, 1H), 4,45 (m, 2H), 4,67(m, 1H), 4,99(m, 1H), for 6.81(s, 1H), 7,22-to 7.84(m, N).

IR (cm-1): 1689 (ν C=O lactam), 1679 (ν C=O lactam), 750.

HPLC (UV): 99%.

2nd stage: tert-Butyl 3-atomic charges-5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenyl-ethyl)-8H-pyrido[4’,3’:4,5]thieno[2, 3-e]-1,4-diazepin-8-carboxylate

The compound obtained in the previous stage (5.8 g, 10 mmol) was poured in acetic anhydride (58 ml) and then heated at 70°C for 2 hours. The reaction mixture is allowed to cool and then pour it into a saturated sodium bicarbonate solution with a concentration of 10% (150 ml). Produce stirring for 30 minutes with subsequent ex what Roccia with ethyl acetate. After desantirovaniya the organic phase is washed with saturated sodium bicarbonate solution with a concentration of 10% (2×150 ml) and then water (2×150 ml). The organic phase is dried over magnesium sulfate and the solvent is evaporated. After purification by chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 20-80 to 50-50) the fractions containing only the product is evaporated. The obtained solid is re-treated in a mixture of solvents: isopropyl ether-isopentane (20-80). After filtration on a Frit and wash isopentane get the desired product in the form of a beige powder (5.2 g, 84%).

IR (cm-1): 3420, 2975, 1742 (ν C=O ester), 1702 (ν C=O carbamate), 1679 (ν C=O lactam), 1233, 1111, 755.

3rd stage: tert-Butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate

The compound obtained in the previous phase (2.5 g, 4.2 mmol), dissolved in methanol (60 ml). The reaction mixture is cooled to -5°S, and then added dropwise a solution of sodium hydroxide (has 0.168 g in 6 ml of water). Produce stirring for 2 hours at 23°C. the Solvent is evaporated, after which the reaction mixture absorb dichloromethane, washed with water and then a saturated solution of ammonium chloride (2×100 ml). After desantirovaniya the organic phase is washed with water, with the shat over magnesium sulfate and the solvent is evaporated. After purification by chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 20-80 to 50-50) the fractions containing only the product is evaporated. After filtration on a Frit and wash isopentane get the desired product in the form of a yellow powder (4.1 g, 87%).

Melting point: 138-140°C.

4th stage: 5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

The product obtained in the previous phase (0.56 g, 1 mmol), dissolved in dichloromethane (8 ml). Add triperoxonane acid (2.5 ml) and stirred for 2 hours at 23°C. the Solvent is evaporated and the resulting oil absorb 5 ml of acetone. Add 20 ml of ether and produce stirring and the precipitate discarded. After filtration on a Frit and washing with ether to obtain the desired product in the form of a beige powder (0.32 g, 56%).

Melting point: 180-189°C.

EXAMPLE 6.

5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

5-(2-Chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he (0.167 g, 0.29 mmol) dissolved in dichloromethane (2 ml). Add triethylamine (0.06 ml, 0.44 mmol) and 4-methoxy-2-nitrophenylacetylene (0,062 g, 0.29 mmol). After stirring at 23°in accordance With the s 2 hours the solvent is evaporated. After purification by chromatography on a column of silica (eluent: a mixture of dichloromethane-methanol: 98-2) the fractions containing only the product is evaporated. Solid absorb ether and added drop by drop dichloromethane and acetone. After filtration on a Frit and washing the solid with ether to obtain the desired product in the form of a yellow powder (0.08 g, 41%).

Melting point: 143-145°C.

EXAMPLE 7.

3-(7-Amino-1-occulations)-5-(2-chlorphenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin

1st stage: tert-Butyl 5-(2-chlorophenyl)-3-[7-[(1,1-dimethylethoxysilane)amino]-1-oxo-heptyloxy]-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno [2,3-e]-1,4-diazepin-8-carboxylate

1 g of tert-butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-3-hydroxy-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5,]thieno[2,3-e]-1,4-diazepin-8-carboxylate (1.8 mmol) are added to a mixture containing 7-[(1,1-dimethylmethoxy)carbonyl]aminoheptanoic acid (0.45 g, 1.8 mmol), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0,42 g of 2.16 mmol), triethylamine (0.25 ml, 2.2 mmol) and 4-dimethylaminopyridine (0,22 g, 1.8 mmol) in dichloromethane (10 ml). Produce stirring for 24 hours at 23°With, then add dichloromethane (30 ml) and ice water (20 ml). Produce stirring and the reaction mixture is left to desantirovaniya. the content of inorganic fillers phase washed with water (2× 20 ml) and dried over magnesium sulfate. After evaporation of the solvent on a rotary evaporator spend chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: 2-98 to 5-95). The fractions containing only the product is evaporated. The desired product is obtained in the form of white amorphous powder (1.0 g, 71%).

Melting point: 90-94°C.

1H NMR (400 MHz, Dl3that δ): 1,24-of 1.62(m, N), 1,95(d, 1H), 2,5(m, 2H), 2,8-2,9(m, 4H), 3(m, 1H), 3,82(m, 1H), 3,86 (m, 1H), 4,35(m, 2H), 4,70(d, 1H), 5,94(s, 1H), 6.73 x(m, 1H), 7,2-7,3(m, 5H), 7,47-7,56(m, 4H).

IR (cm-1): 3381, 2932, 1744 (ν C=O ester), 1704-1677 (ν C=O carbamates and ν C=O lactam), 1165.

HPLC-MS: 99,1% at 250 nm (MN+ found 779,3; MN+ theoretical 779,32).

2nd stage: 3-(7-Amino-1-occulations)-5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

The compound obtained in the previous phase (0.95 g, 1.2 mmol), dissolved in dichloromethane (2 ml). Add triperoxonane acid (1 ml) and stirred for 16 hours at 23°C. After evaporation of the solvent on a rotary evaporator using toluene (2×20 ml) produced purification by chromatography on a column of silica (eluent: a mixture of dichloromethane-methanol-triethylamine: from 90-6-0 to 89-10-1). After evaporation of the fractions containing only the product, get the desired product in the form of a white powder (0,13 g, 19%).

1 H NMR (400 MHz, Dl3that δ): 1,28-of 1.64 (m, 13H), 2-2,2 (m, 1H), 2,52(m, 2H), 2,73-2,87(m, 4H), 3,2-3,4(m, 1H), 3,82(m, 1H), 4.26 deaths-4,37 (m, 2N)-, 5,94(s, 1H), 7,22-7,5-5 (m, N), 7,95(CE, 2H).

HPLC-MS: 96,5% at 250 nm (MS+ found 579,2; MN+ theoretical 579,22).

EXAMPLE 8. 3-(7-Amino-1-occulations)-5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

3-(7-Amino-1-occulations)-5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1, 4-diazepin-2-he (0.11 g, 0.2 mmol) dissolved in dichloromethane (2 ml). Add 4-methoxy-2-nitrophenylacetylene (0,047 g, 0.22 mmol). Produce stirring for 24 hours at 23°With, then add isopropyl ether (20 ml) until precipitation of a solid substance. The heterogeneous mixture is stirred while adding ether (2 ml) and dichloromethane (0.5 ml). After filtration on a Frit and washing with isopropyl ether to obtain the desired product in the form of an orange powder (0,045 g, 29%).

Melting point: 90-95°C.

HPLC-MS: 89,3% at 250 nm (MS+ found 789,2; MN+ theoretical 789,22).

EXAMPLE 9. 4-(7-Amino-1-oxoethyl)-5-(2-chlorophenyl)-1,2,3,6,7,9-octahydro-1-(2-phenylethyl)-NR-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

1st stage: tert-Butyl 5-(2-chlorophenyl)-1,2,3,6,7,9-octahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate

To 4 g of tert-butyl 5-(chlorphenyl)-1,2,3,6,7,9-hexahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate (7.9 mmol) at ambient temperature in an argon atmosphere add acetic acid (12 ml). Then add ethanol (60 ml), after which the reaction mixture is cooled to 0°and slowly add cyanoborohydride sodium (1.5 g, 2.4 mmol). The reaction mixture is stirred for 1 hour at 23°C, then poured into water and then extracted with dichloromethane (2×100 ml). The organic phase is washed with 10% ammonium hydroxide solution (2×50 ml) and dried over magnesium sulfate. After filtration and evaporation of solvent to obtain the desired product in the form of an amorphous white solid (2,96 g, 75%).

1H NMR (400 MHz, Dl3that δ): 1,36(s, N), of 1.65(m, 1H), 2,16 (m, 1H), 2,78(m, 1H), 2.91 in(m, 1H), 3,38(m, 1H), 3,42(m, 2H), 3,50(m, 2H), 4,20(m, 1H), and 4.40(m, 1H), 4,50(m, 1H), 5,46(m, 1H), 7,30(m, 8H), 7,43(m, 1H).

IR (cm-1): 3350 (ν NH, diazepin), 2950, 1687 (ν C=O carbamate), 1672 (ν C=O lactam), 1365, 1172, 751.

HPLC (UV): 99,4%.

2nd stage: tert-Butyl 5-(2-chlorophenyl)-4-[7-[(1,1-dimethylethoxysilane)amino]-1-oxoethyl]-1,2,3,4,5,6,7,9-octahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate

The product obtained in the previous step (1 g, of 1.86 mmol), dissolved in 1,2-dichloroethane (20 ml). Add N-cyclohexylcarbodiimide resin, N’-metropolitical H1 (2.3 g, 5.6 mmol) and tetrahydrofuran (0.5 ml). Add 7-[(1,1-dimethylmethoxy)carbonyl]aminoheptanoic acid (0,91 g, 3.7 mmol) and stirred for 48 hours at 23°C. the Resin is filtered. The solvent issue the mandate and the reaction mixture absorb dichloromethane (30 ml). Add basic ion-exchange resin, and then produce a stirring for 1 hour, followed by filtration. After evaporation of the solvent on a rotary evaporator get the desired product in the form of an amorphous white solid (1.2 g, 86%).

1H NMR (400 MHz, Dl3that δ): 1,15(m), 1,25(m)1,36(C)of 1.41(C)of 1.52(m), 2,85(m)of 2.16(m), 2,22-2,40(m), 2,58(m)2,81(m), 3,48(m in), 3.75(m), 3,90(m), 4,35(m), 4,40-4,60(m)6,0-7,0(m), 7,30(m), 7,18-7,40(m).

IR (cm-1): 3378 (ν NH carbamate), 2974, 2930, 1700 (ν C=O carbamates), 1676 (ν C=O lactam), 1391, 1168, 759.

3rd stage: 4-(7-Amino-1-oxoethyl)-5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-1-(2-phenylethyl)-8H-pyrido [4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

The solution containing the compound obtained in the previous step (1 g, 1.3 mmol), and triperoxonane acid (3 ml) in 10 ml of dichloromethane is stirred for 4 hours at 23°C. the Reaction mixture is evaporated and absorbed toluene (2×30 ml) and ether (2×30 ml). The residue is stirred in a mixture of solvents containing ether-acetone-dichloromethane (90-0,5-0,5) for 5 minutes followed by filtration on a Frit and rinsed with ether. The desired product is obtained in the form of a white powder (1.0 g, 96%).

Melting point: 149-152°C.

1H NMR (400 MHz, Dl3that δ): 1,20-of 1.57(m), 1,86 was 2.25(m), 2,56-and 2.79(m), 2.91 in(m), 3,30(m), 3,79-3,91(m), 4,27-4,37(m), 6,07-6,63(m), 6,63-6,99(m), 7,01-7,76(m), 9,45(m).

EXAMPLE 10. 4-(7-Amino-1-oxoethyl)-5-(2-what lorgeril)-1,2,3,4,5,6,7,9-octahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-phenylethyl)-8H-pyrido [4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

To 0.5 g of 4-(7-amino-1-oxoethyl)-5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5,]thieno[2,3-e]-1,4-diazepin-2-she (to 0.63 mmol)dissolved in dichloromethane (12 ml), add triethylamine (to 0.22 ml, 1.5 mmol). Then add 4-methoxy-2-nitrophenylacetylene (0,146 g, 0.69 mmol) and produce stirring for one hour at 23°C, after which the solvent is evaporated on a rotary evaporator. After purification by chromatography on a column of silica (eluent: a mixture of dichloromethane-methanol-ammonium hydroxide: from 98-2-0 to 95-5-0,5) the fractions containing only the product is evaporated and then add the minimum amount of dichloromethane and then 1M hydrochloric acid (0.2 ml). Produce stirring for 30 minutes at 23°C, after which the resulting product is filtered on a Frit. After washing with ether to obtain the desired product in the form of an orange powder (0.12 g, 25%).

Melting point: 160°C.

1H NMR (400 MHz, Dl3that δ): 1,32(m)of 1.57(m), and 1.9(m), 2,10 (m), 2,33(m), 2,43-2,75(m), 3,57-3,35(m), 3,83(m), 4,35(m)5,00(m), and 5.30(m), 6,65(m)7,00(m), 7,50-7,01 (m), 7,89(m), RS 9.69(m).

IR (cm-1): 3420 (ν NH), 2930, 1670, 1664, 1655, 1649, 1532, 1348.

HPLC (UV): 96%.

EXAMPLE 11. 5-(2-Chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-4-(3-methyl-2-butenyl)-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diaaepam

1st stage: tert-Butyl 5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-4-(3-methyl-2-butenyl)-2-the CSR-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate

0.5 g of tert-butyl 5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate (1 mmol) dissolved in anhydrous tetrahydrofuran (20 ml). Portions add dispersed at a concentration of 60% sodium hydride (0,028 g, 1.1 mmol). Reaction medium leave before the termination of the selection, and then added dropwise 1-bromo-3-methyl-2-butene (0,125 ml, 1.1 mmol). Stirred for 3 hours at 23°and the reaction mixture is heated overnight at 60°With, then add halogenosilanes derived (0,125 ml, 1.1 mmol). After heating for 48 hours at 60°the reaction mixture is then poured into a saturated solution of ammonium chloride (30 ml) and add ethyl acetate (30 ml). After desantirovaniya the aqueous phase is extracted with ethyl acetate (30 ml). The organic phase is dried over magnesium sulfate, filtered and the solvent is evaporated. After purification by chromatography on a column of silica (eluent: a mixture of ethyl acetate-heptane: from 20-80 to 50-50) the fractions containing only the product is evaporated and the desired product is obtained in the form of a pale yellow amorphous powder (0,47 g, 79%).

1H NMR (400 MHz, Dl3that δ): 1,37 (s, N), of 1.53(s, 3H), 1,67(s, 3H), 2.06 to 2,48(m, 2H), 2.49 USD(m, 1H), 2,61(m, 1H), 3,11(m, 2H), 3,23 (m, 1H), 3,3(m, 1H), 3,48(m, 2H), 3,70(m, 1H), 4,46(m, 1H), 4,46(m, 2H), of 5.17(m, 2H), 5,17(m, 2H), 7,17-of 7.55(m, N).

IR (cm-1): 2974, 2926, 2855, 1697 (ν carbamate), 1676 (ν C=O lactam), 1365, 1165, 750, 699.

HPLC (UV): 98.5 PER CENT.

2nd stage: 5-(2-Chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-4-(3-methyl-2-butenyl)-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-2-he

The compound obtained in the previous phase (0.4 g, of 0.65 mmol), dissolved in dichloromethane (5 ml), then add triperoxonane acid (2 ml). Produce stirring for 2 hours at 23°C, after which the solvent and excess acid is evaporated on a rotary evaporator. After purification by chromatography on a column of silica (eluent: a mixture of dichloromethane-methanol-ammonium hydroxide: from 98-0-0 to 98-2-0,2) the fractions containing only the product is evaporated. The remaining oil absorb ether (20 ml). After cooling, add a simple ester of 1 M hydrochloric acid (0.2 ml) and stirred for 15 minutes, then the obtained solid is filtered on a Frit and washed with ether. The desired product is obtained in the form of a pale yellow powder (0.11 g, 33%).

Melting point: 114-118°C.

1H NMR (400 MHz, Dl3that δ): 1.55V(s, 3H), 1.69 in(s, 3H), 2,3-to 2.65(m, 4H), 3,14 is 3.40(m, 7H), 3,68(m, 1H), 3,97(m, 1H), 4,27(m, 2H), 5,14 (m, 2H), 7,16-7,56(m, N), 9,50(m, 2H).

EXAMPLE 12. 5-(2-Chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-4-(3-methyl--2-nitrophenyl)-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

0,22 g of 5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-4-(3-m is Teal-2-butenyl)-1- (2-phenylethyl)-8H-pyrido [4’,3’:4,5]thieno [2, 3-e] -1,4-diazepine-2-it (0.43 mmol) dissolved in dichloromethane (2 ml), then add 4-methoxy-2-nitrophenylacetylene (0.1 g, 0.48 mmol). After stirring for 1 hour at 23°the solvent is evaporated. After purification by chromatography on a column of silica (eluent: a mixture of dichloromethane-methanol: from 100-0 to 99.5 to 0.5) the fractions containing only the product is evaporated and the obtained solid substance absorb the isopentane (20 ml). Add ether (2 ml), and then produce stirring for 20 minutes, followed by filtration on a Frit and rinsed a minimum amount of isopropyl ether and isopentane. The desired product is obtained in the form of a pale yellow powder (0,19 g, 61%).

Melting point: 80-84°C.

1H NMR (400 MHz, Dl3that δ): 1.55V(s, 3H), 1.69 in(s, 3H), 2,25-to 2.67(m, 3H), 3,07-3,26(m, 4H), 3,70(m, 1H), 3,84(s, 3H), of 3.96(m, 2H), 4,10 (m, 1H), 5,00-by 5.18(m, 4H), 6,86-to 7.59(m, 13H), 9,52(s, 1H).

IR (cm-1): 3482, 2974, 2926, 2855, 1671 (ν C=O lactam), 1500, 1302.

HPLC (UV): 98%.

EXAMPLE 13. 5-(2-Chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-1-(2-phenylethyl)-8H-pyrido[4’,3’: 4,5]thieno[2,3-e]-1,4-diazepin-2-he

tert-Butyl 5-(2-chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-2-oxo-1-(2-phenylethyl)-8H-pyrido[4’3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carboxylate (0.5 g, of 0.93 mmol) dissolved in anhydrous dichloromethane (10 ml). Add triperoxonane acid (3 ml) and produce stirring at a temperature of about 20°there within two hours. The solvent is evaporated while absorbing several times with toluene. Add a mixture of solvents (ether-dichloromethane-acetone 30-0,5-0,5 ml), after which the reaction mixture is stirred for two hours and the precipitate discarded. After filtration on a Frit, washing with ether and drying under vacuum get the desired product in the form of a yellow powder (0.34 g, 85%).

Melting point: 128-130°C.

HPLC-MS: 97% at 270 nm (MN+ found 438,1; MN+ theoretical 438,14).

EXAMPLE 14. 5-(2-Chlorophenyl)-1,2,3,4,5,6,7,9-octahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-pentyl)-8H-pyrido[4’,3’:4,5]thieno[2,3-e]-1,4-diazepin-8-carbothioamide

To 0.16 g of 5-(2-chlorophenyl)-1,2,3,6,7,9-hexahydro-N-(4-methoxy-2-nitrophenyl)-2-oxo-1-(2-pentyl)-8H-pyrido[4’,3:4,5]thieno[2,3-e]-1,4-diazepin-8-thioamide group by forming (0.26 mmol) is added acetic acid (0.5 ml). To this yellow suspension add ethanol (3.5 ml), then acetic acid (1 ml) and then added dropwise to cyanoborohydride sodium (0,033 g, 0.52 mmol). The reaction mixture is stirred for 1 hour, after which it was heated for one hour at 40°to dissolve. After that make stirring for 2 hours at 22°C. the Reaction mixture was poured into ice water (30 ml), followed by stirring, filtering and intensive washing with water. After drying in a vacuum without heating the desired product is obtained is in the form of an orange powder (0,145 g, 83%).

Melting point: 90°C.

HPLC-MS: 94% at 240 nm (M is found 614,1%; MN+ theoretical 614,17).

Other compounds obtained in accordance with methods similar to those described in examples 1-14 below. Examples 15-45 illustrate compounds in which A--b is-C=N-; examples 46-70 illustrate compounds in which A--b is-N(R5)-.

The radicals R1; R’1; Y; R2; R3a; R3b; R5; X; n; R’4; R4and the melting point (°not necessarily supplemented by the connection state (fb: free basis; st: salt (TFU); sh: salt (Hcl); *amorphous state) examples 15-45 respectively have the following meanings:

Example 15: N; -; -; 2-Cl-Phe; N; N;; 2; N; Phe; 84-88 (*fb);

Example 16: N; -; -; 2-Cl-Phe; N; N; O; 0; N; phenylcarbinol; 132-134(fb);

Example 17: N; -; -; 2-Cl-Phe; H; N; O; 0; N; Phe; 135-136(fb);

Example 18: N; -; -; 2-Cl-Phe; N; N; O; 0; S; cyclohexyl; 189-190(fb);

Example 19: N; -; -; 2-Cl-Phe; N; N;; 4; N; N; 144-150(fb);

Example 20: N; -; -; 2-Cl-Phe; N; N;; 2; Phe; Phe; 104-108(fb);

Example 21: N; -; -; 2-Cl-Phe; N; N;; 2; Me; Me; 74-77(*fb);

Example 22: N; -; -; 2-Cl-Phe; N; N; O; 0; N; substituted; 222-230(sh);

Example 23: N; -; -; 2-Cl-Phe; N; N; O; 1; N; pyridyl; 82(*fb);

Example 24: N; -; -; Phe; N; N; O; 1; N; Phe; >80(*fb);

Example 25: N; -; -; 4-Cl-Phe; N; N; O; 1; N; Phe; 118-120(fb);

Example 26: N; -; -; 2-F-Phe; N; N; O; 1; Phe; >85(*fb);

Example 27: N; -; -; 4-F-Phe; N; N; O; 1; N; Phe; >70(*fb);

Example 28: N; -; -; 2-Me-Phe; N; N;;; H; Phe; 80-82(*fb);

Example 29: N; -; -; tert-butyl; N; N; O; 1; N; Phe; 160-162(sh);

Example 30: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; H; Phe; 141-143;

Example 31: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; phenylcarbinol; 182-184;

Example 32: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; Phe; 190-192;

Example 33: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 4; n; N; 158-160;

Example 34: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; S; cyclohexyl; 183-184;

Example 35: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Phe; Phe; 156-158;

Example 36: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Me; Me; 149-154;

Example 37: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; substituted; 210-214;

Example 38: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 1; H; pyridyl; 131;

Example 39: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; H; H; O; 1; H; Phe; 148-150;

Example 40: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 4-Cl-Phe; H; H; O; 1; H; Phe; >130 (*);

Example 41: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-F-Phe; H; H; O; 1; H; Phe; >122 (*);

Example 42: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 4-F-Phe; H; H; O; 1; H; Phe; 108-110;

Example 43: R’1-NH-C(Y)-; 2-F3With-h; O; 4-F-Phe; H; H; O; 1; H; Phe; >85 (*);

Example 44: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Me-Phe; H; H; O; 1; H; Phe; 120-130;

Example 45: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; tert-butyl; H; H; O; 1; H; Phe; 177.

The radicals R1; R’1; Y; R2; R3a; R3bX; n; R’4; R4and R5a Ki is the melting point (° With not necessarily supplemented by the connection state (fb: free basis; st: salt (TFU); sh: salt (Hcl); * amorphous state) examples 46-70 respectively have the following meanings:

Example 46: N; -; -; 2-Cl-Phe; N; N; N;; 2; Me; Me; 128-132(sh);

Example 47: N; -; -; 2-Cl-Phe; N; N; aminophenylarsonic;; 1; N; Phe; 200-202(st);

Example 48: N; -; -; 2-Cl-Phe; N; N; indolylmethane;; 1; N; Phe; 160(st);

Example 49: N; -; -; 2-Cl-Phe; N; N; aminobutyryl;; 1; N; Phe; 120-124(st);

Example 50: N; -; -; 2-Cl-Phe; N; N; propylboronic;; 1; N; Phe; 214(st);

Example 51: N; -; -; 2-Cl-Phe; N; N; cyclopentanecarbonyl;; 1; N; Phe; 175-185(st);

Example 52: N; -; -; 2-Cl-Phe; N; N; phenylpropionyl;; 1; N; Phe; >155(st);

Example 53: N; -; -; 2-Cl-Phe; N; N; phenylethylamine;; 1; N; Phe; 149-151(st);

Example 54: N; -; -; 2-Cl-Phe; N; N; 4-(L-alkanoyloxy)benzylcarbamoyl;; 1; N; Phe; >140(st);

Example 55: N; -; -; 2-Cl-Phe; N; N; 4-(aminomethyl)phenylcarbinol;; 1; N; Phe; (fb);

Example 56: N; -; -; Phe; N; N; NH2-CH2-C(O)-NH-CH2-C(O)-NH-C(O) -;; 2; Me; Me; 122-128 (st);

Example 57: N; -; -; neopentyl; N; N; aminohexanoic;; 1; N; Phe; >50;

Example 58: N; -; -; isobutyl; N; N; aminohexanoic;; 1;

H; Phe; 60°With (*);

Example 59: H; -; -; isobutyl; H; H; H;; 1; H; Phe; 202-206 (sh);

Example 60: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; propylboronic;; 1; H; Phe; 163-165;

Example 61: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; cyclopentanecarbonyl;; 1; H; Phe; 177-178;

Example 2: R’ 1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; phenylpropionyl;; 1; H; Phe; 202-203;

Example 63: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; phenylpropionyl;; 1; H; Phe; 114-115;

Example 64: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; aminobutyryl;; 1; H; Phe; 166-172 (sh);

Example 65: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; indolylmethane;; 1; H; Phe; 193-196;

Example 66: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; aminophenylarsonic;; 1; H; Phe; >150 (sh);

Example 67: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; H; H; NH2-CH2-C(O)-NH-CH2-C(O)-NH-C(O)-; O; 2; Me; Me; 184-188(sh);

Example 68: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; H; H; aminohexanoic;; 2; Me; Me; 160-166(sh);

Example 69: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; neopentyl; H; H; aminohexanoic;; 1; H; Phe; 116-118 (bl);

Example 70: R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; isobutyl; H; H; aminohexanoic;; 1; H; Phe; 110° (bl);

Pharmacological research

The study of binding to somatostatin receptors

The affinity of the compounds of the invention to somatostatin receptors person is determined by measuring inhibition of binding of somatostatin-14, labeled with iodine-125 ([125I-Tyr11]SRIF-14), receptors transfected cells SNO-K. Human genes encoding each of the subtypes of somatostatin receptors, sst1, sst2, sst3, sst4 and sst5, were isolated and subcloned (Proc.Natl.Acad.Sci.USA, 1992, 89, 251-255; J.Biol.Chem.,1992, 267, 20422-20428; Mol.Pharmacol., 1992, 42, 2136-2142; Proc.Natl.Acad.Sci.USA, 1993, 90, 4196-4200; Mol.Phatmacol.,1994, 46, 291-298). Were designed expressive vectors were obtained line cloned cells via transfection of cells Cho-K1 mammals. The plasmid pRSV-neo was included as a factor in selection.

Cells Cho-K1, stably expressing somatostatin receptors human cultured in medium RPMI 1640 containing 10% serum fruits calves and 0.4 mg/ml geneticin. Cells collected EDTA at a concentration of 0.5 mm and centrifuged at 500 g for 5 minutes at 4°C. the Precipitate resuspended in 50 mm Tris, pH 7.4 and centrifuged twice at 500 g for 5 minutes at 4°C. the Cells are lysed by the sound, and then centrifuged at 39000 g for 10 minutes at 4°C. the Precipitate resuspended in the same buffer and centrifuged at 50000 g for 5 minutes at 4°C. the Obtained cell membranes stored at -80°until the day of experiments.

Experiments on competitive inhibition of binding of [125I-Tyr11]SRIF-14 is carried out in two Parallels in 96-well plates. Cell membranes in the amount of 10 (sst2 and sst5) or 20 (sst1, sst3 and sst4) µg protein/well were incubated with [1251-Tyr11]SRIF-14 in concentrations of 0.05 nm (sst2) or 0.1 nm (sst1, sst3, sst4 or sst5) for 500 (sst3), 60 (sst1 and sst2), 70 (sst5) or 90 (sst4) minutes at 37°buffer 50 mm HEPES, pH 7.4, containing BSA and 0.2%, MgCl25 mm, Trasylol 200 mg/ml, bacitricin 002 mg/ml, phenylmethylsulfonyl 0.02 mg/ml

Upon completion of the incubation period, free or associated with somatostatin receptors [125I-Tyr11]SRIF-14 were separated in the filtration cell (Filtermate 196, Packard) with a filter plates Unifilter GF/C (Packard), pre-treated with 0.1% polyethylenimine. After washing, 50 mm HEPES under filters radioactivity is measured using a counter Top Count (Packard).

Specific binding was obtained by subtracting nonspecific binding (measured in the presence of 0.1 μm somatostatin-14) from the total binding. The results analyzed by nonlinear regression (MDL), and measured the inhibition constants (Ki) are in the range from 10 to 10000 nm.

1. The compound of General formula I

in racemic or enantiomeric or diastereoisomeric form or mixtures thereof,

in which R1represents a hydrogen atom or a radical of the formula R’1-NH-C(Y)-;

R’1represents a phenyl radical, optionally substituted by one or more identical or different substituents selected from lower alkyl, lower alkoxy, lower alkylthio, lower alkoxycarbonyl, lower alkylsulfonyl, Halonen, trifloromethyl, cryptometrics, hydroxy, nitro, cyano, phenyl, phenoxy, cycloalkyl or heterocycle is Lila;

R3represents lower alkyl, trifluoromethyl or phenyl radical, optionally substituted by one or more identical or different substituents selected from hydroxy, halogen, lower alkyl or lower alkoxy;

X and Y independently represent O or S;

R3Arepresents a hydrogen atom, lower alkyl, hydroxy or a radical of the formula - OC(O)R’3A;

R’3arepresents an alkyl radical containing from 1 to 10 carbon atoms, optionally substituted by a radical of the formula NR3aR’’3awhere NR3aand R’’3aindependently represent a hydrogen atom, lower alkyl, phenyl, lower phenylalkyl, alkylsulphonyl or alkoxycarbonyl;

R3brepresents a hydrogen atom or a lower alkyl radical;

R4represents a radical of the formula -(CH2)n-CHR’4R4;

n represents an integer of 0 to 6;

R’4and R4independently represent a hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkenyl, phenyl, pyridyl, phenylcarbinol or substituted, and these radicals are optionally substituted by one or more identical or different substituents selected from hydroxy, halogen, trifloromethyl, lower alkyl or lower alkoxy;

And---represents-C=N-or-C-N(R 5)-;

R5represents a hydrogen atom, lower alkyl, lower alkenyl or a radical of the formula-C(O)-(CH2)pR’5;

R’5represents a hydrogen atom, aminoacyl, lower alkylamino, di(lower alkyl)amino, cycloalkyl, heteroseksualci, guanidyl, optionally substituted by nitro or by cyano, phenyl, optionally substituted by one or more identical or different substituents selected from alkyl or alkoxyalkyl, where these alkyl or alkoxyalkyl optionally substituted hydroxy or amino group; indolyl or a radical of the formula-NH-C(O)-(CH2)c-NH-C(O)-(CH2)d-NH2;

p represents an integer of 0 to 10;

C or d independently represent an integer 0, 1, 2 or 3;

or salts of these compounds.

2. Compounds of General formula I according to claim 1, in which R’1represents a phenyl radical, optionally substituted by one or more identical or different substituents selected from lower alkoxy, trifloromethyl or nitro; R2represents lower alkyl or phenyl radical, optionally substituted by one or more identical or different substituents selected from halogen or lower alkyl; R3Arepresents a hydrogen atom, hydroxy or a radical of the formula-OC(O)R’3a; R’3arepresents a line is whether branched alkyl radical, containing from 1 to 6 carbon atoms, optionally substituted by one or more radical of the formula NR3aR’’3awhere NR3aand R’’3aindependently represent a hydrogen atom, lower alkyl or alkoxycarbonyl; R3brepresents a hydrogen atom; R’4and R4independently represent a hydrogen atom, lower alkyl, cyclohexyl, phenyl, pyridyl, phenylcarbinol or substituted; And---represents-C=N-.

3. Compounds of General formula I according to claim 2, in which R2represents lower alkyl or phenyl radical, optionally substituted by one or more identical or different groups selected from methyl, chlorine and fluorine; R’3arepresents a linear or branched alkyl containing from 1 to 6 carbon atoms, optionally substituted by one or more identical or different substituents, which are optionally substituted by one or more amino groups.

4. Compounds of General formula I according to one of claims 1 to 3, And in which---is-C=N -, and the radicals R1; R’1; Y; R2; R3A; R3b; X; n; R’4; R4have respectively the following values:

N; -; -; 2-Cl-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; S; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N;; 2; N; Phe;

N; -; -; 2-Cl-Phe; N; N; O; 0; N; phenylcarbinol;

N; -; -; 2-Cl-Phe; N; N; O; 0; N; Phe;

N; -; -; 2-Cl-Pe; N; N; O; 0; S; cyclohexyl;

N; -; -; 2-Cl-Phe; N; N;; 4; N; N;

N; -; -; 2-Cl-Phe; N; N;; 2; Phe; Phe;

N; -; -; 2-Cl-Phe; N; N;; 2; Me; Me;

N; -; -; 2-Cl-Phe; N; N; O; 0; N; substituted;

N; -; -; 2-Cl-Phe; N; N; O; 1; N; pyridyl;

H;-;-;Phe; H; H; O; l; H; Phe;

N; -; -; 4-Cl-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-F-Phe; N; N; O; 1; N; Phe;

N; -; -; 4-F-Phe; N; N; O; 1; N; Phe;

N; -; -; 2-Me-Phe; N; N; O; 1; N; Phe;

N; -; -; tert-butyl; N; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; IT; N; O; 1; N; Phe;

N; -; -; 2-Cl-Phe; OC(O)-(CH2)6NH2; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 2; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; S; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; N; phenylcarbinol;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 4; N; N;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; O; 0; S; cyclohexyl;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N;; 2; Phe; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 0; H; substituted;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; H; H; O; 1; H; pyridyl;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2 -4-MeO-Phe; S; 4-Cl-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 4-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-F3C-Phe; O; 4-F-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Me-Phe; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; tert-butyl; H; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; OH; H; O; 1; H; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; -OC(O)-(CH2)6NH2; H; O; 1; H; Phe;

5. Compounds of General formula I according to claim 1, in which R’1represents phenyl, optionally substituted by one or more identical or different substituents selected from lower alkoxy or nitro; R2represents lower alkyl or phenyl, optionally substituted by one or more identical or different halogen groups; R3Aand R3brepresent a hydrogen atom; R’4and R4independently represent a hydrogen atom, lower alkyl or phenyl radical; And---represents a-C-N(R5)-; R5represents a hydrogen atom, lower alkenyl or a radical of the formula-C(O)-(CH2)p-R’5.

6. Compounds of General formula I, as defined in claim 5, in which R2represents lower alkyl or phenyl, optionally substituted by chlorine; R5represents a hydrogen atom, pentenyl or radicalface - C(O)-R’5; R’5represents a hydrogen atom, amino, cyclopentyl, indolyl, a radical of the formula-NH-C(O)-CH2-NH-C(O)-CH2-NH2or phenyl, optionally substituted by one or more identical or different substituents selected from alkyl or alkoxyalkyl, and these alkyl and alkoxyalkyl optionally substituted hydroxy and amino group.

7. Compounds according to any one of claims 1, 5 or 6, And in which---is-N(R5)and the radicals R1; R’1; Y; R2; R3a; R3b; R5; X; n; R’4; R4have respectively the following values:

H- -; -; 2-Cl-Phe; H; H; H;; 1; H; Phe;

N; -; -; 2-Cl-Phe; H; N; N;; 2; Me; Me;

N; -; -; 2-Cl-Phe; N; N; CH2CH=C(Me)2;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminohexanoic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminophenylarsonic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; indolylmethane;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; aminobutyryl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; propylboronic;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; cyclopentanecarbonyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; phenylpropionyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; phenylethylamine;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; 4-(L-alkanoyloxy)benzyl-carbonyl;; 1; N; Phe;

N; -; -; 2-Cl-Phe; N; N; 4-aminomethylpropanol;; 1; N; Phe;

N; -; -; Phe; N; N; NH2CH 2-C(O)-NH-CH2-C(O)-NH-CH2-C(O) -;; 2; Me; Me;

N; -; -; neopentyl; N; N; aminohexanoic;; 1; N; Phe;

N; -; -; isobutyl; N; N; aminohexanoic;; 1; N; Phe;

N; -; -; isobutyl; N; N; N; O; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; N;; 4; N; N;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; CH2CH=C(Me)2;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminohexyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; propyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; cyclopentylmethyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; phenylpropyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; phenylethyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminobutyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; indoleacetic-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; 2-Cl-Phe; N; N; aminopentyl-carbonyl;; 1; N; Phe;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; N; N; NH2-CH2-C(O)-NH-CH2-C(O)-NH-CH2-C(O) -;; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; Phe; N; N; aminohexyl-carbonyl;; 2; Me; Me;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; neopentyl; N; N; aminohexyl-carbonyl;; 1; H; he;

R’1-NH-C(Y)-; 2-NO2-4-MeO-Phe; S; isobutyl; N; N; aminohexyl-carbonyl;; 1; H; Phe.

8. The method of obtaining compounds of General formula I, as defined in claim 1, And in which---is-C=N-, R1is a hydrogen atom, and R3Ais a hydrogen atom or alkyl, in this way the compound of formula (1)

in which R2and R3bhave the meanings indicated in claim 1;

R3ahas the meaning indicated above;

R’ represents lower alkyl or lower finically radical

enter into reaction with the compound

R4Z,

in which R4has the meaning specified in claim 1;

Z represents a detachable group,

in the presence of a strong base to obtain the compounds of formula (2)

in which X represents an oxygen atom

thus obtained compound (2) is not necessarily subjected to the reaction with the reagent datirovaniya to obtain compound (2)in which X represents a sulfur atom; the compound (2)in which X represents an oxygen atom or sulfur, in the last stage is subjected to reaction removal carbamazapine group to obtain the desired product (I).

9. The method of obtaining compounds of General formula I, as defined in claim 1, and in which---And In a small town in the defaults-C=N-, R1is a hydrogen atom, and R3Ais hydroxy, in this way the compound of the formula (2)as defined in item 8, is subjected to oxidation in an inert solvent to obtain compounds of formula (3)

in which R2, R3A, R4and X have the meanings indicated in claim 1;

R’ has the meaning specified in item 8,

the compound obtained of the formula (3) is treated with acetic anhydride to obtain a compound of the formula (4)

in which R2, R3b, R4, R’ and X have the meanings indicated above;

the obtained compound (4) is then subjected to saponification to obtain the compounds of formula (5)

in which R2, R3b, R4, R’ and X have the meanings indicated above;

the compound (5) at the last stage is subjected to reaction removal carbamazapine group to obtain the corresponding compound of formula (I)in which R1represents H, a R3ais hydroxy.

10. The method of obtaining compounds of General formula I, as defined in claim 1, And in which---is-C=N-, R1is a hydrogen atom, and R3A- radical-OC(O)R’3ain this way the compound of formula (5)as defined in claim 9, is subjected to the interaction with the acid of the formula

R’3aC(O)OH,

in which R’3ahas the meaning specified in claim 1,

to obtain the compounds of formula

in which R2, R’3a, R3b, R4, R’ and X have the meanings indicated above;

the obtained compound (6) are then subjected to reaction removal carbamazapine group to obtain the corresponding compound of formula (I)in which R1is N, and R3A- radical-OC(O)-R’3A.

11. The method of obtaining compounds of General formula I, as defined in claim 1 and in which And---represents a-C-N(R5)-, R1and R5- hydrogen atoms and R3Ais a hydrogen atom or an alkyl radical, in this way the compound of the formula (2)as specified in item 8, enter into reaction with soft regenerating agent in an acidic medium to obtain the compounds of formula (8)

in which R2, R3b, R4and X have the meanings indicated in claim 1;

R3Ahas the meaning indicated above;

R" has the meaning specified in item 8,

the obtained compound (8) is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom.

12. The method of obtaining compounds of General formula I, as defined in claim 1, and in which---And In predstavlyaet-C-N(R 5)-, R1represents a hydrogen atom, R3Ais a hydrogen atom or alkyl, a R5represents alkenyl, in this method, the compound of formula (8)as defined in claim 11, enter into reaction with the compound of the formula

Z’-R5,

in which R5has the meaning indicated above;

Z’ - detachable group,

in the presence of a strong inorganic base in an inert solvent to obtain compounds of formula (9)

in which R2, R3b, R4and X have the meanings indicated in claim 1;

R3Aand R5have the values specified above;

R" has the meaning specified in item 8,

the obtained compound (9) is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom.

13. The method of obtaining compounds of General formula I, as defined in claim 1 and in which And---represents a-C-N(R5)-, R1represents a hydrogen atom, R3ais a hydrogen atom or alkyl, and R5represents a radical of the formula-C(O)-(CH2)p-R’5in this way the compound of formula (8)as defined in claim 11, is introduced into reaction with the acid of the formula

R’5-(CH2)p-C(O)OH,

in which R’5and p have the meanings indicated above,

to obtain the corresponding compounds (10),

in which R2, R3b, R4and X have the meanings indicated in claim 1;

R3A, R’5and p have the meanings indicated above;

R’ has the meaning specified in item 8,

the obtained compound (10) is subjected to reaction withdrawal carbamazapine group to obtain the desired product (I)in which R1represents a hydrogen atom.

14. The method of obtaining compounds of General formula I, as defined in claim 1, in which R1represents a radical of the formula R’1-NH-C(Y), in this way the corresponding compound of formula (I)in which R1represents a hydrogen atom, is introduced into reaction with the compound of the formula

in which R’1and Y have the meanings indicated above,

to obtain the desired compounds of formula (I).

15. Pharmaceutical composition having activity to inhibit the binding of somatostatin-14, containing as active ingredient at least one compound according to any one of claims 1 to 7, in combination with a pharmaceutically acceptable carrier.

16. The compounds of formula I according to any one of claims 1 to 7 to obtain a therapeutic composition for the treatment of pathological conditions or diseases that involve one (and the or more) of somatostatin receptors.

17. The intermediate compound of formula (2)

in which R’ represents lower alkyl or lower phenylalkyl;

R2represents lower alkyl, trifluoromethyl or phenyl, optionally substituted by one or more identical or different substituents selected from hydroxy, halogen, lower alkyl or lower alkoxy;

X represents oxygen;

R3Aand R3bindependently represent a hydrogen atom or alkyl;

R4represents a radical of the formula -(CH2)n-CHR’4R4;

n takes on the values 0, 1, 2, 3, 4, 5 or 6;

R’4and R4independently represent a hydrogen atom, lower alkyl, cycloalkyl, lower cycloalkenyl, phenyl, pyridyl, phenylcarbinol or substituted, these radicals optionally substituted by one or more identical or different substituents selected from hydroxy, halogen, trifloromethyl, lower alkyl or lower alkoxy.



 

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< / BR>
where ring b and F are independently from each other represent a 6-membered carbocyclic ring; R1means H, C1-C4alkyl; AND1and2pairs are selected from the group including =O, N, -OR", where R" denotes N;1and2pairwise mean =O; X in all positions independently from each other selected from the group: a) unsubstituted WITH1-C3alkylen, b) -S-; R3, R4, R5, R6independently from each other selected from the group comprising H1-C4alkyl; compounds 1 can be used for inhibiting protein kinase C (PKC) and inhibit the activity of tyrosine kinase (trk)

--carboline" target="_blank">

The invention relates to bellrowan-carbolines, formula I, where R3denotes-CO-R1or group (a); R1- C1-C6alkoxy; R2- N2C1-C4alkyl, C1-C4alkoxy - C1-C2alkyl; And -- 5-6-membered unsaturated cycle, in which 1-2 carbon atoms may be replaced by N, O and/or S, which may be substituted with one R5or R6; R5and R6identical or different, denote H, C1-C6alkyl, NR7R8C1-C6alkyl which may be substituted by hydroxyl or C1-C4alkoxyl, phenyl, 5-6-membered heteroaryl residue, which contains one or two atoms of N, O or S, and phenyl and heteroaryl residue may be substituted C1-C4the alkyl, C1-C4alkoxyl, halogen, or R5and R6together,- CH2)nwhere n = 4; R7and R8- H, C1-C4alkyl, acyl, as well as their isomers, tautomers and salts

The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

FIELD: metalloorganic chemistry, chemical technology, catalysts.

SUBSTANCE: invention relates to class of metallocene compounds of the general formula (I) wherein Y means fragment of the formula (II) wherein A means sulfur or selenium atom; B means carbon atom; D means carbon atom; R1, R2, R3, R4 and R5 mean hydrogen atom or hydrocarbon groups; Z is taken among fragment of the formula (II) and fragment of the formula (III) wherein R6, R7, R8 and R9 mean hydrogen atom or hydrocarbon groups; L means bivalent bridge group; M means zirconium atom; X means halogen atom; p = 2. Above described metallocenes are useful especially for polymerization of propylene.

EFFECT: improved preparing method, valuable properties of metallocenes.

15 cl, 5 tbl, 18 ex

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to new biologically active chemical substances of some heterocyclic compounds of the formula (1A-C).

where (1a) R=5-brimfull-2; (1B) R=furyl-2; (1B) R=cyclohexyl,

showing property to weaken the toxic effect of the herbicide hormonal action of 2,4-dichlorophenoxyacetic acid (2,4-D) on seedlings of sunflower

The invention relates to new derivatives of amidine General formula (I’)

where it is:

in which R1, R2and R3HE or1-C6alkyl, C1-C6alkoxy, R4- H1-C6alkyl, R5- H1-C6alkyl or the radical:

where R10, R11and R12- OH or H, R13- H1-C6alkyl; or the radical:

where R18, R19and R20- H, HE, C1-C6alkyl, R21and R22- H, C1-C6alkyl, or R21-alkylsulfonyl, alkylsulfonyl, alkylaryl, and R22- H or the radical:

where T is -(CH2)k-, k = 1, 2, R27- H, C1-C6alkyl

The invention relates to new derivatives of amidine General formula (I’)

where it is:

in which R1, R2and R3HE or1-C6alkyl, C1-C6alkoxy, R4- H1-C6alkyl, R5- H1-C6alkyl or the radical:

where R10, R11and R12- OH or H, R13- H1-C6alkyl; or the radical:

where R18, R19and R20- H, HE, C1-C6alkyl, R21and R22- H, C1-C6alkyl, or R21-alkylsulfonyl, alkylsulfonyl, alkylaryl, and R22- H or the radical:

where T is -(CH2)k-, k = 1, 2, R27- H, C1-C6alkyl

The invention relates to new triaromatic the vitamin D analogues of General formula (I):

where R1- CH3or-CH2HE, R2-CH2HE, X-Y - linkage of formula (a) or (C)

where R6- H, lower alkyl, W is O, S or-CH2-, Ar1, Ar2the cycles of formula (e), (j), (k), (m)

R8, R9, R11, R12- H, lower alkyl, halogen, HE, CF3,

R3-

where R13, R14- lower alkyl, CF3, R15- H, acetyl, trimethylsilyl, tetrahydropyranyl, or their salts

The invention relates to new derivatives of 2,3-benzodiazepine of the formula 1

where R1-R4have the meanings specified in the description, has a neuroprotective effect, as well as to methods for their preparation, pharmaceutical compositions and method of treatment of symptoms, followed by all types of acute and chronic neurodegeneration

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